Industry update: Latest developments in stem cell research and regenerative medicine

Business Development

▪ Collaborations, partnerships & alliances

Codevelopment agreement: Cardium Therapeutics, Orbsen Therapeutics & National University of Ireland, Galway

Cardium Therapeutics, CA, USA (www.cardiumthx.com), has entered into an agreement with Orbsen Therapeutics, Ireland (www.orbsentherapeutics.com), and the National University of Ireland, Galway, Ireland (www.nuigalway.ie), to utilize Cardium‘s Excellagen^® pharmaceutically formulated 2.6% fibrillar type I bovine collagen gel as a delivery agent (www.excellagen.com) for Orbsen‘s proprietary stromal cell therapy in preclinical studies for the potential treatment of diabetic foot ulcers.

Collaboration agreement: Cardium Therapeutics & Boston Children‘s Hospital

Cardium Therapeutics, CA, USA (www.cardiumthx.com), and Boston Children‘s Hospital, MA, USA (www.childrenshospital.org), have entered research collaboration to assess the medical utility of Excellagen as a delivery scaffold to seed autologous mesenchymal fetal stem cells for ex vivo engineering of tissue grafts for transplantation into infants to repair prenatally diagnosed birth defects.

Collaboration agreement: International Stem Cell Corporation & Duke University

International Stem Cell Corporation (ISCO), CA, USA (www.internationalstemcell.com), has entered into a master clinical research agreement with Duke University, NC, USA (http://duke.edu), to conduct clinical trials research into Parkinson‘s disease using ISCO‘s innovative neural stem cell product, human parthenogenetic neural stem cells, derived from the company‘s proprietary histocompatible human pluripotent stem cells.

Collaboration agreement: NeoStem & University of California, San Francisco

Neostem, NY, USA (www.neostem.com), and the University of California, San Francisco, CA, USA (www.ucsf.edu), have agreed to collaborate on the development of human regulatory T cells for the treatment of Type 1 diabetes, steroid-resistant asthma and organ transplant rejection.

Distribution agreement: Sanguine BioSciences & AMS Biotechnology

Sanguine BioSciences, CA, USA (www.sanguinebio.com), a biotechnology company enabling personalized medicine research, announced a distribution partnership with AMS Biotechnology, UK (www.amsbio.com), to make its products and services available to researchers in Europe. Sanguine collects and deidentifies biospecimens, medical history and other data from patients diagnosed with severe and chronic diseases for use in biomarker research. Researchers traditionally obtain biospecimens through hospitals, but this process often proves inefficient as the focus for physicians and staff is on diagnosis and treatment, not facilitating research efforts. By connecting directly with patients, Sanguine can meet the needs of researchers and offer timely turnaround of biospecimen and medical data with diverse ranges for age, race, disease state, gender and treatments underway. The patient engagement tactics used by the company have led to a 95% retention rate, which also allows for follow-up draws for longitudinal studies.

Partnership agreement: Fibrocell Science & Intrexon

Fibrocell Science, PA, USA (www.fibrocellscience.com), and Intrexon, VA, USA (www.dna.com), have expanded their partnership. Fibrocell is known for its US FDA-approved product LAVIV^® (azficelT), a wrinkle treatment that involves extracting, multiplying and injecting a patient‘s own fibroblasts back into the patient. The new agreement broadens the existing collaboration to include potential treatments based on engineered autologous fibroblast cells for the localized treatment of autoimmune and inflammatory disorders, including moderate-to-severe psoriasis, aimed at developing a potentially new class of therapeutics.

▪ Launching new projects, products & services

AlloSource

AlloSource, CO, USA (www.allosource.org), a nonprofit provider of skin, bone and soft tissue allografts for use in surgical procedures, launched a new proprietary allograft, AlloMend™ Acellular Dermal Matrix, which can be used in a broad range of soft tissue surgical procedures, including ventral hernia repair and postmastectomy reconstruction. AlloMend is created through a proprietary process in which viable cellular elements that are capable of triggering an immune response are removed from donated human skin, leaving a collagen elastin matrix behind. Upon transplantation, the recipient‘s own cells infiltrate and repopulate this 3D scaffold to begin the revascularization and remodeling process.

Americord

Americord, NY, USA (http://cordadvantage.com), announced a new policy to reimburse parents who have banked stem cells from their baby‘s cord blood with Americord and use the stem cells for a sibling. The reimbursement will be given to parents when their baby‘s cord blood stem cells are used for a sibling in a medical therapy or when the cord blood stem cells are used in a clinical trial as long as a medical professional specifies the use of the cord blood stem cells as medically necessary.

Cellectis SA & Scéil

Cellectis SA, France (www.cellectis.com), launched Scéil™, an offering for the general public that involves storing induced pluripotent stem cells (iPSCs) generated from a skin sample so that people can benefit, if needed, from future regenerative medicine treatments as soon as they become available. Scéil will initially be marketed by a new wholly owned subsidiary of Cellectis SA, Scéil Private Limited (www.sceil.com), in Singapore. Another Scéil subsidiary is being set up in Dubai. The costs are US$60,000, plus US$500 annual storage fee, with the first 2 years of storage being free of charge.

StemCells

StemCells, CA, USA (www.stemcellsinc.com), has formally launched its Alzheimer‘s disease program, which is being supported by the California Institute for Regenerative Medicine (CIRM), CA, USA (www.cirm.ca.gov). The goal of the project is to file, within 4 years, an Investigational New Drug (IND) application with the FDA to evaluate StemCells‘ proprietary HuCNS-SC^® product candidate (purified human neural stem cells) as a potential therapeutic in the treatment of Alzheimer‘s disease. CIRM has agreed to provide approximately US$19.3 million to the Company in the form of a forgivable loan to help fund preclinical development and IND-enabling activities. The Company also recently received an initial disbursement of US$3.8 million from CIRM. The funding was awarded under CIRM‘s Disease Team Therapy Development Award program (RFA 10-05) in September 2012.

▪ Achievements

Fibrocell Science

A University of California, Los Angeles, LA, USA (www.ucla.edu)–Stanford University, CA, USA (www.stanford.edu) collaborative study demonstrated a potential mechanism for converting research-grade adult skin cells into clinical grade iPSCs using two fibroblast lines from Fibrocell Science, PA, USA (www.fibrocellscience.com) [1].

MiMedx Group

MiMedx Group, GA, USA (http://mimedx.com), an integrated developer, manufacturer and marketer of patent-protected regenerative biomaterials and bioimplants processed from human amniotic membrane, has published data on biological properties, the presence of growth factors, interleukins and tissue inhibitors of metalloproteinases, in processed dehydrated human amnion/chorion tissue allografts [2]. The Company also published results of the randomized clinical trial examined the efficacy of dehydrated human amnion/chorion membrane injection as a treatment for the inflammation associated with chronic refractory plantar fasciitis [3]. The study determined that this injection for plantar fasciitis can reduce inflammation and promote healing, and may be an alternative to surgical intervention. Further information about the clinical trial is available at http://clinicaltrials.gov (ClinicalTrials.gov identifier: NCT01659827).

Clinical Trials

▪ Avita Medica

Avita Medical, CA, USA (www.avitamedical.com), enrolled the first three patients in the RESTORE trial, a multicenter, randomized European clinical trial evaluating the use of ReCell^® Spray-On Skin™ in the management of patients with venous leg ulcers. About the same time, it reached the target enrollment in a pilot randomized clinical trial evaluating ReCell Spray-on Skin in patients with skin pigmentation disorders including vitiligo. Further information about Avita‘s ongoing clinical trials with ReCell Spray-on Skin is available at http://clinicaltrials.gov (ClinicalTrials.gov identifiers: NCT01743053, NCT01640678, NCT00615355, NCT01138917 and NCT01476826).

▪ Bellicum

Bellicum Pharmaceuticals, TX, USA (www.bellicum.com), has initiated treatment of the first patient in a study of BPX-201 dendritic cells in combination with activating agent AP1903. The Phase I dose escalation trial in patients with metastatic castrate-resistant prostate cancer was designed to evaluate the safety, tolerability and clinical outcomes of BPX-201 and AP1903, which incorporate the Company‘s second-generation DeCIDe™ immunotherapy technology. The first generation used in BPX-101 provided remote control of CD40 activation signaling, while the second generation adds control of Toll-like receptor costimulation signaling, which helps achieve a more potent antitumor effect. Further information about the clinical trial is available at http://clinicaltrials.gov (ID: NCT01823978).

▪ Calimmune

The HIV gene medicines company Calimmune, CA, USA (www.calimmune.com), announced that the first patient has begun treatment in a Phase I/II clinical trial designed to determine whether a pioneering genetic medicine approach can help to protect individuals infected with HIV from the effects of the virus. In the study, 12 HIV-positive participants will be infused with their own T cells and hematopoietic stem cells, which have been modified to block the HIV receptor CCR5, and to prevent HIV fusion. The procedure is designed to prevent the virus from entering and damaging protected cells. The dual approach used in the study is designed to reduce the possibility that HIV can develop resistance to the procedure. The goal of the study is to assess the safety, feasibility and tolerability of Cal-1 in HIV-infected individuals who have previously been on highly active antiretroviral therapy but are not currently taking any antiretroviral agent. In addition to routine clinical and laboratory assessments to monitor general health and HIV infection, the study will monitor the presence of Cal-1-protected cells in various cell types in the blood and lymphoid tissue. Other analyses will monitor the safety of Cal-1. Data from this study are expected in 2015. Further information about the clinical trial is available at http://clinicaltrials.gov (ID: NCT01734850).

▪ StemCells

StemCells, CA, USA (www.stemcellsinc.com), presented data showing that, 2 years after transplantation of the Company‘s proprietary purified human neural stem cells, HuCNS-SC^®, into patients with Pelizaeus–Merzbacher disease, the evidence of myelination, by MRI, is more pronounced compared with 1-year post-transplantation, the gains in neurological function reported after 1 year were maintained and there were no safety concerns. Patients with Pelizaeus–Merzbacher disease have a defective gene that leads to insufficient myelin in the brain, resulting in progressive loss of neurological function and death. The neurological and MRI changes suggest a departure from the natural history of the disease and may represent signals of a clinical effect. Further information about the clinical trial is available at http://clinicaltrials.gov (ClinicalTrials.gov identifier: NCT01005004).

Regulations, Approvals & Acquisitions

▪ Northwest Biotherapeutics

Northwest Biotherapeutics, MD, USA (www.nwbio.com) has received a decision from the German regulatory agency, the Paul Ehrlich Institute (www.pei.de) allowing the Company‘s Phase III clinical trial with DCVax^®-L for newly diagnosed glioblastoma multiforme to proceed in Germany. DCVax-L mobilizes a cancer patient‘s whole immune system to attack the full set of biomarker targets on the tumor. Further information about the clinical trial is available at http://clinicaltrials.gov (ClinicalTrials.gov identifier: NCT00045968).

▪ Regulations

Philippines

The Philippines Department of Health (www.doh.gov.ph) has given all health facilities practicing stem cell therapy and companies importing and producing stem cell products until 31 August 2013 to apply for accreditation and product registration.

▪ Green light

BioHeart

Bioheart, FL, USA (www.bioheartinc.com), has received a validated registration from the FDA for the initial tissue bank listing. Bioheart is offering stem cell storage for patients enrolled in the studies at the centers of excellence outside the USA. Patients can store stem cell doses in liquid nitrogen for future use in approved clinical trials. These trials focus on the use of adipose derived stem cells, LipiCell™, in a variety of different degenerative diseases.

Cordlife Sciences India

Cordlife Sciences India (www.cordlifeindia.com) has been granted the International Certificate of Accreditation from AABB, MD, USA (www.aabb.org), for activities related to the processing, storage and distribution of cord blood.

Cytori Therapeutics

Cytori Therapeutics, CA, USA (www.cytori.com), has received notice from the Australian Therapeutic Goods Administration (www.tga.gov.au) that the Celution^® System is approved for commercial use through inclusion on the Australian Registry of Therapeutic Goods for autologous reimplantation or reinfusion of a patient‘s adipose-derived regenerative cells (ADRCs). The Celution^® System produces autologous ADRCs at the point of care, which may then be used for patients with a range of injuries or conditions.

France

French parliament has passed a new law allowing embryo research and embryo stem cell tissue research in spite of strong opposition from both right wing and religious groups.

Japan

Japan‘s government gave its seal of approval to the world‘s first clinical trials using iPSCs aimed at treating age-related macular degeneration, a common medical condition that causes blindness in older people. The study is led by the Riken Center for Developmental Biology in Kobe, Japan (www.cdb.riken.jp/en/index.html), which will be the world‘s first clinical application of hiPSC technologies for regenerative medicine for humans, opened patient recruitment on 1 August 2013.

Mesoblast

Mesoblast, Australia (www.mesoblast.com), has received approvals from Australian ethics committees to commence a Phase II trial evaluating a single intravenous infusion of its proprietary allogeneic or ‘off-the-shelf‘ adult mesenchymal precursor cells (MPCs) in patients with Type 2 diabetes and advanced kidney disease, or diabetic nephropathy. Ethics approvals for the two selected doses were obtained after safety data were reviewed from the ongoing 60-patient Phase II trial evaluating a single intravenous infusion of MPCs in people with early Type 2 diabetes without kidney disease. Further information about that trial can be found at http://clinicaltrials.gov (ClinicalTrials.gov identifier: NCT01576328).

Promethera Biosciences

Promethera Biosciences, Belgium (www.promethera.com), received a positive opinion from the EMA relating to the designation of HepaStem as an orphan medicinal product for the treatment of seven urea cycle deficiencies (UCDs): hyperargininemia, carbamoyl-phosphate synthetase-1 deficiency, hyperornithinemia–hyperammonemia–homocitrullinuria syndrome, citrullinemia type 2, argininosuccinic aciduria, citrullinemia type 1 and N-acetylglutamate synthetase deficiency. UCDs are a group of inborn errors of metabolism that affect the transfer of nitrogen into urea. Eight metabolic disorders are associated with a defect in the gene encoding each urea cycle enzyme. In May 2008, an orphan drug designation was already granted for HepaStem for the treatment of ornithine transcarbamylase deficiency disease, the most frequent form of UCD. HepaStem is a cell suspension constituted of heterologous human adult liver progenitor cells isolated from normal adult human liver tissue.

SynGen

SynGen, CA, USA (www.syngeninc.com), has been granted FDA 510(k) clearance to market its three related products to process cord blood:

• ▪ SynGenX™-1000 System: a programmable control module, docking station and disposable cartridge for harvesting stem and progenitor cells from units of collected cord blood;

• ▪ CryoPRO-2™ Cryopreservation/Storage Bag Set;

• ▪ SynGen™ DataTrak software.

Tisch MS Research Center

Tisch MS Research Center, NY, USA (http://tischms.org), has received IND approval from the FDA to commence a Phase I trial using autologous neural stem cells in the treatment of multiple sclerosis. Stem cells, harvested from the patient‘s own bone marrow, will be injected intrathecally into 20 participants who meet the inclusion criteria for the trial.

Vital Therapies

Vital Therapies, CA, USA (http://vitaltherapies.com), a biopharmaceutical company focused on developing a cell-based therapy targeting the treatment of acute liver failure, announced that the European Commission granted Orphan Medicinal Product Designation for C3A cells for the treatment of acute liver failure. These cells, which the company grows from its proprietary cell bank, serve as the active ingredient in ELAD^®, the Company‘s investigational artificial liver therapy.

▪ Pending

California Stem Cell

California Stem Cell, CA, USA (www.californiastemcell.com), submitted a Phase III protocol to the FDA for a randomized, double-blind study in metastatic melanoma. The multicenter trial will examine the effectiveness of patient cancer-specific stem cell-based immunotherapy in patients with recurrent stage III or IV metastatic melanoma.

▪ Acquisitions

Capricor & Nile Therapeutics, Inc.

Capricor, CA, USA (www.capricor.com), a privately held biotechnology company developing cardiac stem cell therapeutics, and Nile Therapeutics, Inc., CA, USA (www.nilethera.com), have entered into a Merger Agreement under which Capricor will become a wholly owned subsidiary of Nile Therapeutics, Inc. in an all-stock transaction. Upon closing, the combined company will be named Capricor Therapeutics, Inc., and will operate under the leadership of the Capricor management team with the Company‘s board of directors having representatives from both the existing Capricor and Nile boards.

EcoQuest & Cynata

EcoQuest, Australia (www.ecoquest.com.au), is to add a stem cell technology to its globally focused environmental and life sciences portfolio through the acquisition of Australian company Cynata (http://cynata.com). Cynata has an exclusive worldwide license to commercialize the use of mesenchymoangioblasts, a type of adult stem cells involved in building cardiovascular system.

ThermoGenesis & TotipotentRx

ThermoGenesis, CA, USA (www.thermogenesis.com), is paying US$18.6 million to buy TotipotentRx, CA USA (www.totipotentrx.com). TotipotentRx specializes in cell-based therapy, whereas ThermoGenesis develops and sells technologies for processing and storing stem cells and tissue. The combined company will take on a new name, Cesca Therapeutics, and it will keep the ThermoGenesis ticker KOOL. The name Cesca comes from ‘clinical excellence in stem cell applications‘. TotipotentRX, CA, USA (www.totipotentrx.com), and ThermoGenesis together with Fortis Memorial Research Institute, India (www.fmri.in), launched pediatric bone marrow transplant program.

Capital Market & Finances

▪ Athersys

Athersys, OH, USA (www.athersys.com), has received a Small Business Innovation Research (SBIR) Fast Track grant from the National Heart, Lung and Blood Institute (www.nhlbi.nih.gov), which will support a Phase II clinical study evaluating the administration of MultiStem^® therapy to patients who have suffered an acute myocardial infarction. The grant is expected to provide up to US$2.8 million in support over the course of the study in connection with study progress and milestone achievement.

▪ Axogen

AxoGen, FL, USA (www.axogeninc.com), a company focused on the commercialization of proprietary products and technologies for peripheral nerve reconstruction and regeneration, closed an underwritten offering of 6,000,000 shares of its common stock at a price to the public of US$3.00 per share. The Company received gross proceeds of approximately US$18 million, excluding the underwriters‘ overallotment option and deductions for underwriting discounts and commissions, and estimated expenses.

▪ Cellular Dynamics International

Cellular Dynamics International, WI, USA (www.cellulardynamics.com), a developer and manufacturer of fully functioning human cells in industrial quantities to precise specifications, closed initial public offering of 3,846,000 shares of common stock at a price to the public of US$12.00 per share. The underwriters had a 30-day option to purchase up to an additional 576,900 shares of common stock from the Company. The offering raised proceeds to the Company of approximately US$43 million, after deducting underwriting discounts and commissions.

▪ CFD Research Corporation

CFD Research Corporation, AL, USA (www.cfdrc.com), has been awarded a 2-year US$1 million contract from the US Department of Defense‘s Defense Health Program (http://cdmrp.army.mil/dmrdp) to continue their research into the detection and sorting of stem cells according to their differentiation states.

▪ Cytori Therapeutics

Cytori Therapeutics, CA, USA (www.cytori.com), has entered into a US$15 million three-part agreement with Bimini Technologies, CA, USA (http://biminitechnologies.com), and its affiliates, Kerastem Technologies and Puregraft Technologies (www.kerastem.com). First, Cytori has sold global manufacturing and commercialization rights for the Puregraft^® product line. In exchange, Cytori has received a US$5 million upfront payment and will receive up to an additional US$10 million from commercial milestones related to future Puregraft sales. In addition, Bimini has acquired global, exclusive rights to commercialize the Celution^® System for alopecia. Under the commercial agreement, Bimini will be responsible for all clinical studies, regulatory approvals and market development activities for alopecia and will pay Cytori perpetual royalties on sales. Finally, Bimini has acquired an exclusive option to license Celution products for the global esthetics market. The option is effective until 31 December 2013. Bimini is a newly formed company and is based in San Diego (CA, USA). Bradford Conlan, who has been part of the Cytori team for nearly 9 years, developing and marketing both the Puregraft and Celution products, is the founding CEO of Bimini, as well as its affiliates Puregraft Technologies and Kerastem Technologies. Puregraft is an FDA-approved fat grafting product that allows patients to receive injections of their own fat in a single outpatient procedure. Cytori originally developed Puregraft to be used in combination with its cell therapy technology. Given its simplicity and performance, Cytori has been offering Puregraft as a stand-alone product to physicians in the USA, Asia and Europe since 2010.

▪ Mesoblast

Mesoblast, Australia (www.mesoblast.com), has received approximately US$3.85 (AUD$4.3) million under the Australian Government‘s Innovation Australia R&D Tax Incentive Program for R&D activities conducted in Australia during the 2012 financial year. The funds will be used to advance development of Mesoblast‘s proprietary MPC technology platform and product pipeline.

▪ Nikon Corporation & Retina Institute Japan

Nikon Corporation, Japan (www.nikon.com), signed an agreement to invest in Retina Institute Japan (RIJ; http://rijapan.jp). Under the agreement, Nikon will subscribe for ¥500 million worth of shares issued by RIJ. Together, Nikon and RIJ will collaborate on developing practical uses of medical treatments for age-related macular degeneration. RIJ has been working on the world‘s first case of regenerative medicine using iPSC technology, utilizing Nikon‘s own core technology in optics and imaging.

▪ ReNeuron

ReNeuron, UK (www.reneuron.com), has raised a total of US$51.2 million (GB£33 million) in a financing package.

▪ Stratatech

Stratatech, WI, USA (www.stratatech.com), has been awarded a contract valued at up to US$47.2 million by the US Department of Health and Human Service‘s Biomedical Advanced Research and Development Authority (BARDA; www.phe.gov/about/barda/Pages/default.aspx). The contract is for the advanced clinical and manufacturing development of StrataGraft^® skin tissue, the Company‘s flagship skin replacement product, as a medical countermeasure to treat patients with severe thermal burns. The 5-year contract contains a 2-year base period, with contract options that extend an additional 3 years. The total award will support the preclinical, clinical, regulatory and technology development activities needed to complete the FDA approval process for use of StrataGraft skin tissue to treat thermal burn injury. In addition, the contract funds manufacturing process development and scale-up so that the Company will be positioned for large-scale production volumes that will be needed in case of a mass casualty event as well as for general commercial needs.

▪ Tengion

Tengion, NC, USA (www.tengion.com), closed transactions totaling US$33.6 million to fund its two lead clinical programs, the Neo-Kidney Augment™ and the Neo-Urinary Conduit™. A US$15 million payment in cash was a strategic investment from Celgene, NJ, USA (www.celgene.com). Tengion also plans to issue additional common stock to help satisfy US$861,699 in interest payments to investors that provided pivotal financing since early 2012.

▪ ViaCyte

ViaCyte, CA, USA (www.viacyte.com), has completed a private equity financing transaction, providing the Company US$10.6 million through the sale of Series C-1 Preferred Stock, together with warrants to purchase stock. The financing, conducted as a rights offering to ViaCyte Series B and C Preferred Stock holders, included the Company‘s largest existing investors – Johnson & Johnson Development Corporation (www.jjdevcorp.com), Sanderling Ventures (www.sanderling.com) and asset management company Johnson Trust (http://johnsoninv.com/JohnsonTrustCompany.aspx). This funding serves as a match for US$10.1 million Strategic Partnership Award that was approved in October 2012 by the California Institute for Regenerative Medicine (CIRM; www.cirm.ca.gov) to support clinical evaluation of VC-01, ViaCyte‘s promising encapsulated cell therapy product being developed as a transformative therapy for patients with Type 1 and insulin-dependent Type 2 diabetes.

▪ Vidergen

The UK Technology Strategy Board, under its Regenerative Medicine and Cell Therapy competition, awarded US$3 million (GB£2 million) to a tracheal replacement project, led by Videregen, UK (www.videregen.com). Videregen will use the funds to progress a promising clinical prototype through a rigorous development process and early clinical trials for the treatment of severe structural airway disease.